In multiple human cancers, the function of the eukaryotic translation initiation factor 4E (eIF4E) is elevated and directly related to disease progression. eIF4E binds the 7-methylguanosine cap at the 5′ end of cellular mRNAs, delivering the mRNA to the eIF4F complex to enable ribosome loading and eventual protein translation. The eIF4F complex is comprised of the scaffolding protein eIF4G, the ATP-dependent helicase eIF4A and eIF4E. Once loaded onto the 5′ end of an mRNA, the eIF4F complex is thought to scan 5′-3′, unwinding secondary structure in the mRNA 5′ untranslated region (UTR) to reveal the initiation codon for ribosome loading.
The majority of cellular mRNAs (e.g., β-actin) contain a relatively short and unstructured (limited C+G content) 5′ UTR, through which the eIF4F complex can easily scan to reveal the translation initiation codon. These “strong” mRNAs are therefore efficiently translated, even when eIF4F is limiting. Conversely, “weak” mRNAs (e.g., VEGF, c-myc) have longer 5′ UTR sequences with multiple open reading frames and complex hairpin secondary structures that encumber efficient scanning and require greater energy expenditure to unravel. These mRNAs are thereby inefficiently translated except under conditions of elevated eIF4F activity, as in cancer. In addition, recent work has now shown that eIF4E can mediate the enhanced nucleocytoplasmic transport of select “weak” mRNAs involved in cell growth, including cyclin D. In cancer, eIF4F activity is elevated either by increased eIF4E expression or by enhanced signaling through the ras/PI3K/AKT/TOR axis or both. This consequently enables a disproportionate increase in the translation of these weak mRNAs, many of which are involved in cell growth (cyclin D1), cell survival (survivin, Bcl-2, Mcl-1) or angiogenesis (VEGF, FGF-2).
eIF4E was first defined as a proto-oncogene after its over-expression induced cellular transformation and tumorigenesis in mouse fibroblasts. Subsequently, inhibition of eIF4E expression by ectopic expression of antisense RNA or 4EBP1 was shown to suppress not only tumor formation but also tumor invasiveness and metastasis. Analyses of many different tumor types have now revealed that eIF4E expression is elevated in lymphomas as well as cancers of the breast, lung, head and neck, esophagus, skin, bladder, colon, cervix and prostate. Invariably, such over-expression has been related to disease progression and poorer patient survival. Inhibition of eIF4E is therefore an attractive target for anti-cancer therapeutics and also interestingly a potentially target for treatment of autism as well. Here linkage of autism to the EIF4E region on chromosome 4q has been found in genome wide linkage studies.
A recent report has indicated that the small molecule ribavirin might interfere with the eIF4E:cap interaction and may therefore present a clinical opportunity as an eIF4E-targeted therapy. As anticipated, ribavirin treatment selectively diminished the expression of key, eIF4E-dependent proteins such as cyclin D1 and suppressed tumor growth. However, whether or not ribavirin actually binds eIF4E is controversial. Consequently, a more directed approach to develop small molecule inhibitors of the eIF4E:7-methylguanosine cap interaction might be a fruitful approach for the development of an eIF4E-specific small molecule therapy. To date, no such drug-like inhibitors of the eIF4E-cap interaction have been reported.
An alternative approach to targeting the eIF4E-cap interaction is to selectively disrupt the interaction of eIF4E with eIF4G, thereby disabling the formation of the eIF4F complex. An alternative approach to targeting eIF4E would be to reduce eIF4E protein expression using antisense oligonucloetides (ASOs). eIF4E ASOs have been shown to effectively reduce both eIF4E RNA and protein in a wide array of transfected human and murine cells, subsequently reducing the expression of the malignancy-related proteins-specifically cyclin D1, VEGF, c-myc, survivin and BCL-2. Importantly, ASO mediated reduction of eIF4E did not affect the expression of β-actin, a protein encoded by a “strong” mRNA nor did it reduce overall protein synthesis substantially.
It is therefore an object of the present invention to provide a eIF4E binding peptide that can be efficiently used for the treatment or prevention of cancer and autism.